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Clinical Cancer Research Vol. 12, 5764-5769, October 1, 2006
© 2006 American Association for Cancer Research


Cancer Therapy: Clinical

Analysis of Epidermal Growth Factor Receptor Gene Mutation in Patients with Non–Small Cell Lung Cancer and Acquired Resistance to Gefitinib

Takayuki Kosaka1,6, Yasushi Yatabe2, Hideki Endoh6, Kimihide Yoshida3, Toyoaki Hida3, Masahiro Tsuboi4, Hirohito Tada5, Hiroyuki Kuwano6 and Tetsuya Mitsudomi1,2

Authors' Affiliations: Departments of 1 Thoracic Surgery, 2 Pathology and Molecular Diagnostics, and 3 Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Japan; 4 Department of Surgery, Tokyo Medical University, Tokyo, Japan; 5 Division of General Thoracic Surgery, Osaka City General Hospital, Osaka, Japan; and 6 Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Japan

Requests for reprints: Tetsuya Mitsudomi, Department of Thoracic Surgery, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan. Phone: 81-52-762-6111; Fax: 81-52-764-2963; E-mail: mitsudom{at}aichi-cc.jp.

Purpose: Non–small cell lung cancers carrying activating mutations in the gene for the epidermal growth factor receptor (EGFR) are highly sensitive to EGFR-specific tyrosine kinase inhibitors. However, most patients who initially respond subsequently experience disease progression while still on treatment. Part of this "acquired resistance" is attributable to a secondary mutation resulting in threonine to methionine at codon 790 (T790M) of EGFR.

Experimental Design: We sequenced exons 18 to 21 of the EGFR gene to look for secondary mutations in tumors with acquired resistance to gefitinib in 14 patients with adenocarcinomas. Subcloning or cycleave PCR was used in addition to normal sequencing to increase the sensitivity of the assay. We also looked for T790M in pretreatment samples from 52 patients who were treated with gefitinib. We also looked for secondary KRAS gene mutations because tumors with KRAS mutations are generally resistant to tyrosine kinase inhibitors.

Results: Seven of 14 tumors had a secondary T790M mutation. There were no other novel secondary mutations. We detected no T790M mutations in pretreatment specimens from available five tumors among these seven tumors. Patients with T790M tended to be women, never smokers, and carrying deletion mutations, but the T790M was not associated with the duration of gefitinib administration. None of the tumors had an acquired mutation in the KRAS gene.

Conclusions: A secondary T790M mutation of EGFR accounted for half the tumors with acquired resistance to gefitinib in Japanese patients. Other drug-resistant secondary mutations are uncommon in the EGFR gene.




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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
Copyright © 2006 by the American Association for Cancer Research.